Lung cancer is the leading cause of death worldwide. Each year an estimated 175,000 new cases of lung cancer will be diagnosed, accounting for over 157,000 deaths annually in the USA. Despite advances in the treatment strategies for lung cancer the overall survival rate is less than 6-months. This is due to the inability to control local spread of the tumor as well as failure to treat tumors that have metastasized to distant sites. Thus, there is an urgent need for developing a therapeutic that not only inhibits primary tumor growth but also tumors that have metastasized to distant sites. Therefore, novel forms of treatment modalities are mandated. One such novel therapeutic approach is the utilization of an agent that functions both, as an antitumor agent targeting the tumor and as an anti-angiogenic agent directed at inhibiting tumor vascularization. Thus a gene that can control both, primary tumor and tumor metastatic at a distant site can be an effective therapeutic agent for cancer treatment. One such newly identified molecule is the melanoma differentiation associated gene-7 (mda-7) also known as interleukin-24 (IL-24). The antitumor activity of mda-7 gene against a spectrum of cancer cells is well documented both, in vitro and in vivo. Preliminary studies indicate that the MDA-7/IL-24 protein is secreted (sMDA-7/IL-24) and inhibited endothelial cell or capillary "tube"-Iike structures, an in vitro correlate of angiogenesis. Based on these preliminary observations we hypothesize that sMDA-7/IL-24 possess anti-angiogenic activity. To further test our hypothesis the proposed studies will focus on the following four specific aims: Aim 1: Investigate the anti-angiogenic activity of sMDA-7/IL-24 on endothelial cells in vitro. Aim 2: Investigate whether the anti-angiogenic activity of sMDA-7/IL-24 is receptor mediated. Aim 3: Evaluate the mechanism by which sMDA-7/IL-24 inhibits angiogenesis. Aim 4: Evaluate the in vivo efficacy of sMDA-7/IL-24 in tumor model studies. The experiments designed in this proposal will use molecular and cellular models to assess the antiangiogenic activity. The experiments designed in this proposal will demonstrate that sMDA-7/IL-24 has potent anti-angiogenic activity and will provide the foundation for further development of mda-7 as an anticancer therapeutic that will ultimately result in translation to the clinic.